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Search Results: 1 - 10 of 224961 matches for " Lonny R. Levin "
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Physiological Sensing of Carbon Dioxide/Bicarbonate/pH via Cyclic Nucleotide Signaling
Jochen Buck,Lonny R. Levin
Sensors , 2011, DOI: 10.3390/s110202112
Abstract: Carbon dioxide (CO2) is produced by living organisms as a byproduct of metabolism. In physiological systems, CO2 is unequivocally linked with bicarbonate (HCO3?) and pH via a ubiquitous family of carbonic anhydrases, and numerous biological processes are dependent upon a mechanism for sensing the level of CO2, HCO3, and/or pH. The discovery that soluble adenylyl cyclase (sAC) is directly regulated by bicarbonate provided a link between CO2/HCO3/pH chemosensing and signaling via the widely used second messenger cyclic AMP. This review summarizes the evidence that bicarbonate-regulated sAC, and additional, subsequently identified bicarbonate-regulate nucleotidyl cyclases, function as evolutionarily conserved CO2/HCO3/pH chemosensors in a wide variety of physiological systems.
Identification of a haem domain in human soluble adenylate cyclase
Sabine Middelhaufe,Martina Leipelt,LonnyR. Levin,Jochen Buck
Bioscience Reports , 2012, DOI: 10.1042/bsr20120051
Abstract: The second messengers cAMP and cGMP mediate a multitude of physiological processes. In mammals, these cyclic nucleotides are formed by related Class III nucleotidyl cyclases, and both ACs (adenylate cyclases) and GCs (guanylate cyclases) comprise transmembrane receptors as well as soluble isoforms. Whereas sGC (soluble GC) has a well-characterized regulatory HD (haem domain) that acts as a receptor for the activator NO (nitric oxide), very little is known about the regulatory domains of the ubiquitous signalling enzyme sAC (soluble AC). In the present study, we identify a unique type of HD as a regulatory domain in sAC. The sAC-HD (sAC haem domain) forms a larger oligomer and binds, non-covalently, one haem cofactor per monomer. Spectral analyses and mutagenesis reveal a 6-fold co-ordinated haem iron atom, probably with non-typical axial ligands, which can bind both NO and CO (carbon monoxide). Splice variants of sAC comprising this domain are expressed in testis and skeletal muscle, and the HD displays an activating effect on the sAC catalytic core. Our results reveal a novel mechanism for regulation of cAMP signalling and suggest a need for reanalysis of previous studies on mechanisms of haem ligand effects on cyclic nucleotide signalling, particularly in testis and skeletal muscle.
Somatic ‘Soluble’ Adenylyl Cyclase Isoforms Are Unaffected in Sacytm1Lex/Sacytm1Lex ‘Knockout’ Mice
Jeanne Farrell, Lavoisier Ramos, Martin Tresguerres, Margarita Kamenetsky, Lonny R. Levin, Jochen Buck
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003251
Abstract: Background Mammalian Soluble adenylyl cyclase (sAC, Adcy10, or Sacy) represents a source of the second messenger cAMP distinct from the widely studied, G protein-regulated transmembrane adenylyl cyclases. Genetic deletion of the second through fourth coding exons in Sacytm1Lex/Sacytm1Lex knockout mice results in a male sterile phenotype. The absence of any major somatic phenotype is inconsistent with the variety of somatic functions identified for sAC using pharmacological inhibitors and RNA interference. Principal Findings We now use immunological and molecular biological methods to demonstrate that somatic tissues express a previously unknown isoform of sAC, which utilizes a unique start site, and which ‘escapes’ the design of the Sacytm1Lex knockout allele. Conclusions/Significance These studies reveal increased complexity at the sAC locus, and they suggest that the known isoforms of sAC play a unique function in male germ cells.
Activation of Soluble Adenylyl Cyclase Protects against Secretagogue Stimulated Zymogen Activation in Rat Pancreaic Acinar Cells
Thomas R. Kolodecik, Christine A. Shugrue, Edwin C. Thrower, Lonny R. Levin, Jochen Buck, Fred S. Gorelick
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041320
Abstract: An early feature of acute pancreatitis is activation of zymogens, such as trypsinogen, within the pancreatic acinar cell. Supraphysiologic concentrations of the hormone cholecystokinin (CCK; 100 nM), or its orthologue cerulein (CER), induce zymogen activation and elevate levels of cAMP in pancreatic acinar cells. The two classes of adenylyl cyclase, trans-membrane (tmAC) and soluble (sAC), are activated by distinct mechanisms, localize to specific subcellular domains, and can produce locally high concentrations of cAMP. We hypothesized that sAC activity might selectively modulate acinar cell zymogen activation. sAC was identified in acinar cells by PCR and immunoblot. It localized to the apical region of the cell under resting conditions and redistributed intracellularly after treatment with supraphysiologic concentrations of cerulein. In cerulein-treated cells, pre-incubation with a trans-membrane adenylyl cyclase inhibitor did not affect zymogen activation or amylase secretion. However, treatment with a sAC inhibitor (KH7), or inhibition of a downstream target of cAMP, protein kinase A (PKA), significantly enhanced secretagogue-stimulated zymogen activation and amylase secretion. Activation of sAC with bicarbonate significantly inhibited secretagogue-stimulated zymogen activation; this response was decreased by inhibition of sAC or PKA. Bicarbonate also enhanced secretagogue-stimulated cAMP accumulation; this effect was inhibited by KH7. Bicarbonate treatment reduced secretagogue-stimulated acinar cell vacuolization, an early marker of pancreatitis. These data suggest that activation of sAC in the pancreatic acinar cell has a protective effect and reduces the pathologic activation of proteases during pancreatitis.
Characterization of Plasmodium falciparum Adenylyl Cyclase-β and Its Role in Erythrocytic Stage Parasites
Eric Salazar, Erin M. Bank, Nicole Ramsey, Kenneth C. Hess, Kirk W. Deitsch, Lonny R. Levin, Jochen Buck
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039769
Abstract: The most severe form of human malaria is caused by the parasite Plasmodium falciparum. The second messenger cAMP has been shown to be important for the parasite’s ability to infect the host’s liver, but its role during parasite growth inside erythrocytes, the stage responsible for symptomatic malaria, is less clear. The P. falciparum genome encodes two adenylyl cyclases, the enzymes that synthesize cAMP, PfACα and PfACβ. We now show that one of these, PfACβ, plays an important role during the erythrocytic stage of the P. falciparum life cycle. Biochemical characterization of PfACβ revealed a marked pH dependence, and sensitivity to a number of small molecule inhibitors. These inhibitors kill parasites growing inside red blood cells. One particular inhibitor is selective for PfACβ relative to its human ortholog, soluble adenylyl cyclase (sAC); thus, PfACβ represents a potential target for development of safe and effective antimalarial therapeutics.
CO2 Acts as a Signalling Molecule in Populations of the Fungal Pathogen Candida albicans
Rebecca A. Hall,Luisa De Sordi,Donna M. MacCallum,Hüsnü Topal,Rebecca Eaton,James W. Bloor,Gary K. Robinson,Lonny R. Levin,Jochen Buck,Yue Wang,Neil A. R. Gow,Clemens Steegborn,Fritz A. Mühlschlegel
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001193
Abstract: When colonising host-niches or non-animated medical devices, individual cells of the fungal pathogen Candida albicans expand into significant biomasses. Here we show that within such biomasses, fungal metabolically generated CO2 acts as a communication molecule promoting the switch from yeast to filamentous growth essential for C. albicans pathology. We find that CO2-mediated intra-colony signalling involves the adenylyl cyclase protein (Cyr1p), a multi-sensor recently found to coordinate fungal responses to serum and bacterial peptidoglycan. We further identify Lys 1373 as essential for CO2/bicarbonate regulation of Cyr1p. Disruption of the CO2/bicarbonate receptor-site interferes selectively with C. albicans filamentation within fungal biomasses. Comparisons between the Drosophila melanogaster infection model and the mouse model of disseminated candidiasis, suggest that metabolic CO2 sensing may be important for initial colonisation and epithelial invasion. Our results reveal the existence of a gaseous Candida signalling pathway and its molecular mechanism and provide insights into an evolutionary conserved CO2-signalling system.
The Novel CFTR Mutation A457P in a Male with a Delayed Diagnosis of Cystic Fibrosis
Kate H. Cole,Patrick R. Sosnay,Lonny B. Yarmus,Jonathan B. Zuckerman
Case Reports in Medicine , 2011, DOI: 10.1155/2011/903910
Abstract: Cystic fibrosis (CF) is an autosomal recessive disease that may be caused by more than 1000 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the case of a CF patient who was initially diagnosed at 16 years of age after presenting with mild respiratory compromise and pancreatic sufficiency. When genetic testing was first performed using a CF mutation panel, only a single F508del CFTR allele was identified. We subsequently performed testing, which revealed a previously unreported mutation: A457P (p.Ala457Pro, c.1369G>C). The patient's clinical course through adulthood is described, and genotype-phenotype correlation is discussed. The A457P mutation appears to confer a relatively mild phenotype, as is usually observed with CFTR class IV–VI defects. With the advent of more comprehensive and widely available genetic testing techniques, identification of CF genotypes in patients with milder disease variants may help stratify patients for targeted therapy and prevent late complications of the disease.
Endemicity, Biogeography, Composition, and Community Structure On a Northeast Pacific Seamount
Craig R. McClain, Lonny Lundsten, Micki Ream, James Barry, Andrew DeVogelaere
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004141
Abstract: The deep ocean greater than 1 km covers the majority of the earth's surface. Interspersed on the abyssal plains and continental slope are an estimated 14000 seamounts, topographic features extending 1000 m off the seafloor. A variety of hypotheses are posited that suggest the ecological, evolutionary, and oceanographic processes on seamounts differ from those governing the surrounding deep sea. The most prominent and oldest of these hypotheses, the seamount endemicity hypothesis (SMEH), states that seamounts possess a set of isolating mechanisms that produce highly endemic faunas. Here, we constructed a faunal inventory for Davidson Seamount, the first bathymetric feature to be characterized as a ‘seamount’, residing 120 km off the central California coast in approximately 3600 m of water (Fig 1). We find little support for the SMEH among megafauna of a Northeast Pacific seamount; instead, finding an assemblage of species that also occurs on adjacent continental margins. A large percentage of these species are also cosmopolitan with ranges extending over much of the Pacific Ocean Basin. Despite the similarity in composition between the seamount and non-seamount communities, we provide preliminary evidence that seamount communities may be structured differently and potentially serve as source of larvae for suboptimal, non-seamount habitats.
Nasty Viruses, Costly Plasmids, Population Dynamics, and the Conditions for Establishing and Maintaining CRISPR-Mediated Adaptive Immunity in Bacteria
Bruce R. Levin
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001171
Abstract: Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR) abound in the genomes of almost all archaebacteria and nearly half the eubacteria sequenced. Through a genetic interference mechanism, bacteria with CRISPR regions carrying copies of the DNA of previously encountered phage and plasmids abort the replication of phage and plasmids with these sequences. Thus it would seem that protection against infecting phage and plasmids is the selection pressure responsible for establishing and maintaining CRISPR in bacterial populations. But is it? To address this question and provide a framework and hypotheses for the experimental study of the ecology and evolution of CRISPR, I use mathematical models of the population dynamics of CRISPR-encoding bacteria with lytic phage and conjugative plasmids. The results of the numerical (computer simulation) analysis of the properties of these models with parameters in the ranges estimated for Escherichia coli and its phage and conjugative plasmids indicate: (1) In the presence of lytic phage there are broad conditions where bacteria with CRISPR-mediated immunity will have an advantage in competition with non-CRISPR bacteria with otherwise higher Malthusian fitness. (2) These conditions for the existence of CRISPR are narrower when there is envelope resistance to the phage. (3) While there are situations where CRISPR-mediated immunity can provide bacteria an advantage in competition with higher Malthusian fitness bacteria bearing deleterious conjugative plasmids, the conditions for this to obtain are relatively narrow and the intensity of selection favoring CRISPR weak. The parameters of these models can be independently estimated, the assumption behind their construction validated, and the hypotheses generated from the analysis of their properties tested in experimental populations of bacteria with lytic phage and conjugative plasmids. I suggest protocols for estimating these parameters and outline the design of experiments to evaluate the validity of these models and test these hypotheses.
Study of the simplest realistic Higgs sector in quark-lepton symmetric models
Y. Levin,R. R. Volkas
Physics , 1993, DOI: 10.1103/PhysRevD.48.5342
Abstract: A discrete symmetry between quarks and (generalized) leptons can exist in nature, and its spontaneous symmetry breaking scale can be as low as a few TeV. Such a discrete symmetry also has interesting implications for how electroweak symmetry is spontaneously broken, because the simplest version of the theory requires two electroweak Higgs doublets rather than one in order to provide acceptable values for quark and lepton masses. The effective theory generated at electroweak-scale energies is thus a particular type of two-Higgs-doublet model. We point out in this paper that the broken discrete symmetry imposes very interesting constraints on the form of the Yukawa couplings between physical Higgs bosons and quarks and leptons. In particular, we find that the flavour-changing neutral Higgs couplings to down-sector quarks are proportional to the neutrino Dirac mass matrix. If neutrinos are Dirac particles, then the severe experimental upper bounds on their mass values renders tree-level neutral flavour-changing Higgs effects on down-quark systems like $K^0-\bar{K}^0$ negligibly small. We also discuss minimization of some relevant Higgs potentials and some other pertinent phenomenological issues.
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